Long-Term Study to Evaluate the Safety and Efficacy in Participants With Primary Biliary Cholangitis of Saroglitazar Magnesium-V on Clinical Outcomes

A Phase 3b/4, Multicenter, Parallel Group, Double Blind, Placebo Controlled, Two Arm, Long Term Study to Evaluate the Safety and Efficacy of Saroglitazar Magnesium on Clinical Outcomes in Participants with Primary Biliary Cholangitis (PBC)

Inclusion criteria

Each participant must meet all of the following criteria to be enrolled in this study:

• Is capable of understanding the written informed consent, provides signed and witnessed written informed consent, and agrees to comply with protocol requirements
• Is an adult male or female, must be ≥18 years of age at the time of signing informed consent
• Is receiving ursodeoxycholic acid (UDCA) for ≥12 months with a stable dose for ≥6 months prior to screening,and expected to remain on a stable dose during the study period OR Is unable to tolerate UDCA and did not receive UDCA in the past 3 months prior to screening
• Has a history of confirmed PBC diagnosis, as demonstrated by the presence of ≥2 of the following 3 diagnostic factors:

i. A history of elevated ALP levels for ≥6 months prior to screening ii. Positive antimitochondrial antibodies (AMA) titer OR if AMA is negative, then positive PBC-specific antibodies iii. Liver biopsy consistent with PBC diagnosis

• Has documented evidence of cirrhosis and has ALP >ULN and TB ≤5 × ULN

Exclusion criteria

Participants meeting any of the following criteria will be excluded from the study:

• Has consumption of 2 standard alcohol drinks per day (or 14 alcohol drinks per week) if male and 1 standard alcohol drink per day (or 7 alcohol drinks per week) if female for ≥3 consecutive months (12 consecutive weeks) within 5 years prior to screening
• Has known CPT B (having a score of ≥7) or CPT C (having a score of ≥10) cirrhosis classification at screening
• Has a Model for End-Stage Liver Disease (MELD)-Na score of ≥12 at screening
• Has a history or presence of any of the following other concomitant liver diseases at screening:

i. Chronic hepatitis B or C virus (HBV, HCV) infection. (Note: If a participant has been treated for the HCV infection and has been cured for a duration of >2 years prior to screening, they can be enrolled in the study. Participants who have seroconverted (hepatitis B surface antigen-negative and hepatitis B surface antibody-positive) may be included in this study.

ii. Primary sclerosing cholangitis iii. Alcohol-associated liver diseases iv. Autoimmune hepatitis (AIH)-PBC overlap syndrome v. Hemochromatosis vi. Metabolic dysfunction-associated steatohepatitis on historical biopsy vii. α-1 antitrypsin deficiency

• Has a history or presence of clinically significant hepatic decompensation, including the following:

i. Liver transplantation or currently placed on a liver transplant list ii. Complications of cirrhosis iii. Hepatorenal syndrome (Type I or II) iv. Known or suspected hepatocellular carcinoma or other hepatobiliary malignancies

• Use of the following medications (within 12 weeks prior to screening until the randomization [Day 1] visit): thiazolidinediones, fibrates, OCA, methotrexate, budesonide, and other systemic corticosteroids (equivalent to prednisone dose >10 mg); potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazid, and nitrofurantoin); any other newly approved treatments for PBC (eg, elafibranor, seladelpar)
• Has elevated baseline ALT, AST, or ALP values; ALT, AST, or ALP values increasing by >50% on Visit 2 compared to Visit 1
• Has any of the following laboratory values:

i. TB >5 × ULN ii. Platelets <50 × 10^9/L iii. Albumin <2.8 g/dL iv. ALP >10 × ULN v. Estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m^2 vi. ALT or AST >5 × ULN vii. International normalized ratio (INR) >1.7 in the absence of anticoagulant therapy viii. CPK > 2x ULN

• Has participated in another interventional clinical study and received any other investigational medication or medical device within 30 days or 5 half lives, whichever is longer, prior to screening
• Has a history of malignancy in the past 5 years and/or active neoplasm, which may diminish life expectancy (except resolved superficial nonmelanoma skin cancer, carcinomas in situ, or other stable, relatively benign conditions prior to screening)
• Has a known allergy, hypersensitivity, or intolerance to saroglitazar or any of the formulation ingredients
• Pregnancy-related exclusions, including the following:

i. If a female, who is pregnant (including a positive pregnancy test at screening), breastfeeding, intends to become pregnant, or is a woman of childbearing potential and not agreeing to use adequate contraceptive methods for the duration of the study and for at least 1 month after receiving the last dose of the IP ii. Male participants with WOCBP partners and female participants must avoid pregnancy either by true abstinence or the use of acceptable, effective contraceptive measures for the duration of the study and for at least 1 month after receiving the last dose of the IP

• Has a history or other evidence of severe illness or any other conditions, including cardiovascular, endocrine, hematological, gastrointestinal, neurological, or psychiatric disease, that, in the opinion of the investigator, would make the participant unsuitable for the study